Inflammatory cardiomyopathy - diagnosis and risk stratification in myocarditis

Background: Acute myocarditis remains a challenging clinical diagnosis with limited epidemiological data and poorly defined markers of adverse risk. We sought to build a better understanding of myocarditis epidemiology and to integrate clinical, genetic and advanced imaging data to generate new insights into myocarditis pathobiology. Methods and Results: (1) Evaluation of population-level hospital admission data from NHS England from 1998-2017 revealed a rising incidence of myocarditis, at least two-fold greater than that reported from pathological registries, most commonly amongst men with median age 36 years and women aged 46 years, with distinct peaks over Winter and the greatest burden in London. (2) Cardiovascular magnetic resonance (CMR) phenotype study of a 114 prospectively recruited patients with acute myocarditis demonstrated the natural history of changes in left ventricular parameters over 12 months and revealed a correlation between change in myocardial mechanics, specifically circumferential strain, and extent of myocardial oedema by T2 mapping (R=-0.70, p=0.01). (3) Genetic sequencing of 231 unrelated patients recruited with acute myocarditis revealed the presence of truncating variants in key cardiomyopathy genes in 4.8% of the cohort, particularly linked to arrhythmogenic ventricular cardiomyopathy (AVC) with significant enrichment compared with 1054 healthy volunteers indicating a potential overlap between myocarditis and AVC (odds ratio 8.2; 95% CI 2.4-28.3; p=0.001). (4) Retrospective long-term clinical outcome study of 401 patients with mid-wall/subepicardial late gadolinium enhancement (LGE) but otherwise normal LV volumes and function suggestive of healed myocarditis demonstrated a low risk of actual or aborted sudden cardiac death over a median follow-up of 4.3 years (incidence rate per 100 patient-years of 0.05%). (5) Psychological study of post-traumatic stress disorder amongst 231 patients with acute myocarditis compared with 44 patients with acute myocardial infarction highlighted the profound and long-lasting psychological morbidity associated uniquely with myocarditis. Conclusion: Myocarditis is a heterogeneous disease that remains vastly underestimated in prevalence. Integration of advanced CMR techniques with genomic data may provide incremental value in early diagnosis, non-invasive surveillance and identification of high-risk individuals who may benefit from a more personalised approach with close monitoring and targeted therapy.Open Acces

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.

Background: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. Methods: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Results: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9–7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). Conclusions: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.post-print738 K

Advanced Cardiac Resuscitation Evaluation (ACRE): A randomised single-blind controlled trial of peer-led vs. expert-led advanced resuscitation training

<p>Abstract</p> <p>Background</p> <p>Advanced resuscitation skills training is an important and enjoyable part of medical training, but requires small group instruction to ensure active participation of all students. Increases in student numbers have made this increasingly difficult to achieve.</p> <p>Methods</p> <p>A single-blind randomised controlled trial of peer-led vs. expert-led resuscitation training was performed using a group of sixth-year medical students as peer instructors. The expert instructors were a senior and a middle grade doctor, and a nurse who is an Advanced Life Support (ALS) Instructor.</p> <p>A power calculation showed that the trial would have a greater than 90% chance of rejecting the null hypothesis (that expert-led groups performed 20% better than peer-led groups) if that were the true situation. Secondary outcome measures were the proportion of High Pass grades in each groups and safety incidents.</p> <p>The peer instructors designed and delivered their own course material. To ensure safety, the peer-led groups used modified defibrillators that could deliver only low-energy shocks.</p> <p>Blinded assessment was conducted using an Objective Structured Clinical Examination (OSCE). The checklist items were based on International Liaison Committee on Resuscitation (ILCOR) guidelines using Ebel standard-setting methods that emphasised patient and staff safety and clinical effectiveness.</p> <p>The results were analysed using Exact methods, chi-squared and t-test.</p> <p>Results</p> <p>A total of 132 students were randomised: 58 into the expert-led group, 74 into the peer-led group. 57/58 (98%) of students from the expert-led group achieved a Pass compared to 72/74 (97%) from the peer-led group: Exact statistics confirmed that it was very unlikely (p = 0.0001) that the expert-led group was 20% better than the peer-led group.</p> <p>There were no safety incidents, and High Pass grades were achieved by 64 (49%) of students: 33/58 (57%) from the expert-led group, 31/74 (42%) from the peer-led group. Exact statistics showed that the difference of 15% meant that it was possible that the expert-led teaching was 20% better at generating students with High Passes.</p> <p>Conclusions</p> <p>The key elements of advanced cardiac resuscitation can be safely and effectively taught to medical students in small groups by peer-instructors who have undergone basic medical education training.</p

Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multiparametric quantitative cardiac magnetic resonance imaging.

Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the Toll-like receptor 7 (TLR-7) agonist Resiquimod induces auto-antibodies and systemic tissue damage, including in the heart, and is used as an inducible mouse model of systemic lupus erythematosus (SLE). Here, we show that overactivation of the TLR-7 pathway of viral recognition by Resiquimod treatment of CFN mice induces severe thrombocytopenia and internal bleeding, which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2 * relaxation times, and compared results with ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2 * measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes. In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as an acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2 * mapping to CMR protocols for myocarditis diagnosis improves diagnostic sensitivity and interpretation of disease mechanisms.This article has an associated First Person interview with the first author of the paper

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005)

Outcome in Dilated Cardiomyopathy Related to the Extent, Location, and Pattern of Late Gadolinium Enhancement.

OBJECTIVES: This study sought to investigate the association between the extent, location, and pattern of late gadolinium enhancement (LGE) and outcome in a large dilated cardiomyopathy (DCM) cohort. BACKGROUND: The relationship between LGE and prognosis in DCM is incompletely understood. METHODS: The authors examined the association between LGE and all-cause mortality and a sudden cardiac death (SCD) composite based on the extent, location, and pattern of LGE in DCM. RESULTS: Of 874 patients (588 men, median age 52 years) followed for a median of 4.9 years, 300 (34.3%) had nonischemic LGE. Estimated adjusted hazard ratios for patients with an LGE extent of 0 to 2.55%, 2.55% to 5.10%, and >5.10%, respectively, were 1.59 (95% confidence interval [CI]: 0.99 to 2.55), 1.56 (95% CI: 0.96 to 2.54), and 2.31 (95% CI: 1.50 to 3.55) for all-cause mortality, and 2.79 (95% CI: 1.42 to 5.49), 3.86 (95% CI: 2.09 to 7.13), and 4.87 (95% CI: 2.78 to 8.53) for the SCD endpoint. There was a marked nonlinear relationship between LGE extent and outcome such that even small amounts of LGE predicted a substantial increase in risk. The presence of septal LGE was associated with increased mortality, but SCD was most associated with the combined presence of septal and free-wall LGE. Predictive models using LGE presence and location were superior to models based on LGE extent or pattern. CONCLUSIONS: In DCM, the presence of septal LGE is associated with a large increase in the risk of death and SCD events, even when the extent is small. SCD risk is greatest with concomitant septal and free-wall LGE. The incremental value of LGE extent beyond small amounts and LGE pattern is limited

Sex‐ and age‐based differences in the natural history and outcome of dilated cardiomyopathy

Aim: To evaluate the relationship between sex, age and outcome in dilated cardiomyopathy (DCM). Methods and results: We used proportional hazard modelling to examine the association between sex, age and all‐cause mortality in consecutive patients with DCM. Overall, 881 patients (290 women, median age 52 years) were followed for a median of 4.9 years. Women were more likely to present with heart failure (64.0% vs. 54.5%; P = 0.007) and had more severe symptoms (P 60 years of age was driven by non‐sudden death. Conclusion: Women with DCM have better survival compared to men, which may partly be due to less severe left ventricular dysfunction and a smaller scar burden. There is increased mortality driven by non‐sudden death in patients >60 years of age that is less marked in women. Outcomes with contemporary treatment were favourable, with a low incidence of sudden death

Phenotype and Clinical Outcomes of Titin Cardiomyopathy.

BACKGROUND: Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification. OBJECTIVES: The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM. METHODS: In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events. RESULTS: Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/- groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82). CONCLUSIONS: In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis